Intramolecular N–O Bond Formation for the Synthesis of N-Alkyl and N-Aryl Isoxazolidines

We describe the synthesis of a series of readily assembled, variously substituted 3-(4-trifluoromethyl-2-nitrobenzenesulfonamido)alkyl silylperoxides and their conversion to the corresponding isoxazolidines in moderate to high yield by intramolecular N–O bond formation on removal of the sulfonamide protecting group. Cyclization with N–O bond formation was dependent on steric hindrance of the electrophilic silylperoxides, with primary systems cyclizing directly during the course of sulfonamide cleavage with thiolate anions. Secondary silyl peroxides, on the other hand, were best cyclized by warming in the presence of hexafluoroisopropanol after desulfonylation, while tertiary silylperoxides required deprotonation of the intermediate amine. Tertiary benzylic peroxides underwent cyclization by a novel mechanism, with the formation of intermediate trifluoromethylnitrophenyl peroxides, during the course of fluoride-mediated desilylation. The cyclization was extended to include the formation of a simple oxazine, but extrapolation to the formation of an oxazepine was foiled by competing Kornblum DeLaMare fragmentation at the level of the intermediate aminoperoxide.